Bisphosphonates are a group of drugs that are in clinical use for treatment of osteoporosis and bone malignancies. Circulating bisphosphonates bind to bone mineral and, as the bone is resorbed by osteoclasts, bisphosphonates are internalized and interfere with cell metabolism—leading to apoptosis of the osteoclast (Rogers 2003). Systemic treatment with bisphosphonates can postpone the resorption of a bone graft (Åstrand and Aspenberg 2002, Tägil et al. 2004). In osteonecrosis, bisphosphonates have been shown to delay the resorption of revascularizing dead bone, both experimentally (Little et al. 2003, Kim et al. 2005) and in clinical series (Nishii et al. 2006, Ramachandran et al. 2007). In a randomized human study, bisphosphonates were found to substantially reduce the risk of secondary osteoarthritis in patients with femoral head osteonecrosis (Lai et al. 2005), with only 2 of 29 collapsing in the treated group compared to 19 of 25 in the placebo group. We wanted to determine whether it is also possible to prevent joint surface collapse in spontaneous osteonecrosis of the knee by using a bisphosphonate.

The 15 unoperated patients were treated with bisphosphonates for mean 11 (6–21) months until the defect in the center of the lesion was considered to increase in density and medication was stopped. In 1 patient, a subchondral fracture was seen in the osteonecrotic lesion before treatment started. In this patient, the joint surface did not collapse and the lesion eventually healed with Ahlbäck grade 1 osteoarthritis and minor symptoms (Figure 2).

In the 10 patients who never developed osteoarthritis, the mean Lotke index in plain radiographs at the first visit was 17% (0–60) and in MRI it was 35% (16–58). The lesions gradually increased during treatment and Lotke index peaked in the plain radiographs at a mean of 25% (0–58) before gradually decreasing. The 4 patients who developed osteoarthritis (Ahlbäck grade 1–2) but no collapse had a mean Lotke index in plain radiographs of 14% (0–33) and 23% (19–27) by MRI; it reached a maximum radiographic Lotke index of 30% (21–33). The 3 knees that collapsed had a mean Lotke index at the first visit of 10% (0–18) on plain radiographs and 26% (21–30) by MRI. The maximum Lotke index peaked at 35% (23–50).

In the previous study of 40 patients at our hospital (Al-Rowaih et al. 1991) with a similar but untreated series of knee osteonecrosis, patients with higher Lotke indices had worse outcome with a high frequency of joint surface collapse and subsequent surgery than those in the present, treated series. Only 10 of 40 patients had a good outcome in the original study with complete radiographical recovery, as compared to 10 of 17 in the present series (p = 0.03, Fisher’s exact test). 8 of 40 patients were considered intermediate due to development of osteoarthritis, but with minor symptoms compared to the present study where 4 of 17 of the bisphosphonate-treated patients developed mild osteoarthritis.

The incidence of secondary surgery appears to be less when bisphosphonates are given. In the original series, 22 of 40 patients were considered failures due to osteoarthritis and major symptoms. Of these patients, 13 underwent surgery with osteotomy, decompression, or prosthesis. In the present series, 2 of the 17 patents were failures because they needed surgery (p = 0.2, Fisher’s exact test). It is notable that none of these patients were able to complete the planned minimum 6 months of bisphosphonate treatment and they were the only patients not to do so. Although not operated, another patient in the bisphosphonate-treated group was considered a failure, as he developed severe osteoarthritis (Ahlbäck grade 3) and collapse of the joint surface. In the original series, the size of the lesion was found to be associated with an inferior outcome but in the present series no such association was found. In our series, lesions larger than the cutoff at Lotke index 30% healed without osteoarthritis, but lesions smaller in size also collapsed. In addition, time from the start of symptoms to start of treatment appeared to be unrelated to outcome.

In the only randomized trial using bisphosphonates in osteonecrosis (of the hip) (Lai et al. 2005), a fixed treatment time of 6 months was set. In our study, treatment was continued until the central region started to increase in radiographic density, indicating osteoblast activity in the center and a hypothetically regained mechanical strength. It is not known how long treatment should last.